Alkene dipeptide isosteres are useful amide bond surrogates for controlling peptide conformation. To probe substituent effects in alkene dipeptide isosteres, we designed Arg–Gly–Gly–Tyr peptidomimetics in which the Gly–Gly peptide bond was replaced with either a methylalkene dipeptide isostere or a chloroalkene dipeptide isostere. Solution structures were analyzed using NOESY experiments and amide temperature-coefficient measurements. The methylalkene-type peptidomimetic exhibits NMR features consistent with a g-turn-like conformation, whereas the chloroalkene-type peptidomimetic displays a distinct folded geometry approaching a-/e-turn-like structures. These results indicate that subtle differences in the alkene substituent can induce switching of the preferred turn geometry within an identical peptide sequence. Such substituent-dependent effects highlight the potential of ADIs as backbone-editing elements for controlling peptide turn geometry.

J. Org. Chem., accepted.

Herein, we report a visible-light photoredox-catalyzed reductive ring-opening of g-(2-chloroaziridinyl)acrylates using Hantzsch esters,providing catalytic access to (Z)-chloroalkene dipeptide isosteres (CADIs). The reaction proceeds under mild conditions with high Z-selectivity and broad functional group tolerance, affording Xaa–Gly-type (Z)-CADIs that mimic the trans-amide geometry. Furthermore, the use of 4-alkyl Hantzsch esters enables direct access to CADIs bearing a-alkyl substituents. This method provides an alternative to conventional organocuprate-mediated CADI synthesis.

J. Org. Chem., accepted.